Journal of Medical Genetics最新文献

Exploring the spectrum of central nervous system tumours in carriers of germline POT1 variants. 探索种系POT1变异携带者的中枢神经系统肿瘤谱。

IF 3.7 2区医学

Journal of Medical Genetics Pub Date : 2025-10-24 DOI: 10.1136/jmg-2025-110679

Emilie Neerup Nielsen, Anne Marie Jelsig, Jon Foss-Skiftesvik, Zuzana Lohse, Susanne Timshel, Line Borgwardt, Thomas Van Overeem Hansen, Karin A W Wadt

{"title":"Exploring the spectrum of central nervous system tumours in carriers of germline POT1 variants.","authors":"Emilie Neerup Nielsen, Anne Marie Jelsig, Jon Foss-Skiftesvik, Zuzana Lohse, Susanne Timshel, Line Borgwardt, Thomas Van Overeem Hansen, Karin A W Wadt","doi":"10.1136/jmg-2025-110679","DOIUrl":"https://doi.org/10.1136/jmg-2025-110679","url":null,"abstract":"Background: Pathogenic variants in the protection of telomerase 1 (POT1) gene are associated with predisposition to a broad spectrum of malignancies, although the specific genotype-phenotype correlation has not yet been fully elucidated. To further characterise the phenotypic spectrum, we describe six families with germline POT1 variants and evaluate existing literature to highlight the possible association between variants in POT1, telomere dysregulation and predisposition to malignant central nervous system (CNS) tumours.Methods: Genetic analyses were performed using an Illumina sequencing platform. All variants were examined by in silico analysis in Alamut as well as Rare Exome Variant Ensemble Learner (REVEL), and one variant was additionally examined by RNA analysis.Telomere length assessment was performed through RepeatDX Europe.Results: We identified four missense and two frameshift POT1 germline variants: c.255G>C, p.(Lys85Asn), c.322G>A, p.(Gly108Arg), c.323G>A, p.(Gly108Glu), c.676C>T, p.(His226Tyr), c.707del, p.(Gly236Glufs*16) and c.709del, p.(Ser237Alafs*15). The variants c.255G>C and c.322G>A were observed in two patients with astrocytoma and c.676C>T in a patient with oligodendroglioma, corresponding to the most prevalent CNS tumour histopathology described in POT1 carriers in previous publications. Longer telomeres were found in probands with the CNS tumour phenotype.Conclusion: Our findings support a possible association between pathogenic POT1 germline variants and increased risk of CNS tumours mainly oligodendroglioma, astrocytoma and glioblastoma. We highlight the potential importance of missense variants and telomeric measurement in tailoring of surveillance and advocate further studies to guide future personalised surveillance strategies.","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145368162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PURA protein mislocalisation in the nucleus: mechanistic basis for transcriptional dysregulation and DNA unwinding deficits in a model of the p.L148Wfs*77 PURA variant. PURA蛋白在细胞核中的错误定位：p.L148Wfs*77 PURA变异模型中转录失调和DNA解绕缺陷的机制基础。

IF 3.7 2区医学

Journal of Medical Genetics Pub Date : 2025-10-22 DOI: 10.1136/jmg-2025-110818

Yan Wang, Ping Wang, Jingjing He, He Wang, Shanling Liu

{"title":"PURA protein mislocalisation in the nucleus: mechanistic basis for transcriptional dysregulation and DNA unwinding deficits in a model of the p.L148Wfs*77 PURA variant.","authors":"Yan Wang, Ping Wang, Jingjing He, He Wang, Shanling Liu","doi":"10.1136/jmg-2025-110818","DOIUrl":"https://doi.org/10.1136/jmg-2025-110818","url":null,"abstract":"Background: Heterozygous PURA (Purine-rich element-binding protein A) variants cause PURA syndrome, a neurodevelopmental disorder characterised by hypotonia, seizures and intellectual disability. Previous studies have focused on the effect of the PURA variant in the cytoplasmic location, but nuclear mislocalisation remains to be explored.Methods: We identified a de novo heterozygous frameshift variant (c.442del, p.L148Wfs*77) via trio whole-exome sequencing in one child suspected of PURA syndrome due to intellectual disability. Functional analyses included structural modelling, subcellular localisation assays, RNA-seq, CUT&Tag and DNA unwinding assays.Results: The variant disrupts PURA repeats II-III, causing aberrant nuclear mislocalisation. RNA-seq revealed 688 differentially expressed genes enriched in neurodevelopmental pathways. CUT&Tag analysis revealed that PURA and Pol II exhibit enhanced binding at transcription start sites in cells expressing the variant, indicating dysregulated transcriptional engagement. Despite retained nucleic acid binding, the variant impaired DNA unwinding partly due to disrupted repeat III-mediated homodimerisation.Conclusions: Nuclear mislocalisation of the PURA variant dysregulates transcriptional balance and impairs DNA unwinding, linking PURA's structural integrity to neurodevelopmental deficits. This highlights PURA's dual roles in cytoplasmic RNA regulation and nuclear transcription, providing mechanistic insights into PURA syndrome pathogenesis.","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145354787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dental agenesis as a novel phenotypical feature associated with hereditary diffuse gastric cancer in China. 牙发育不全是中国遗传性弥漫性胃癌的一个新的表型特征。

IF 3.7 2区医学

Journal of Medical Genetics Pub Date : 2025-10-22 DOI: 10.1136/jmg-2025-111081

Ziyue Wang, Qianwen Ding, Jiaqi Xu, Liyan Xue, Lin Dong

{"title":"Dental agenesis as a novel phenotypical feature associated with hereditary diffuse gastric cancer in China.","authors":"Ziyue Wang, Qianwen Ding, Jiaqi Xu, Liyan Xue, Lin Dong","doi":"10.1136/jmg-2025-111081","DOIUrl":"https://doi.org/10.1136/jmg-2025-111081","url":null,"abstract":"Background: Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant gastric cancer associated with germline CDH1 mutations. Carriers of CDH1 mutations have a higher risk of developing gastric cancer at a younger age, highlighting the need for a phenotypic feature for early diagnosis and management.Methods: We analysed 121 patients with gastric cancer who underwent genetic testing at the National Cancer Center in China. CDH1 mutation status was assessed using next-generation sequencing. Fisher's exact test and Mann-Whitney U test were performed to compare clinicopathological features between CDH1-mutated and non-mutated patient groups.Results: Among 121 index cases, three CDH1 germline mutation carriers (2.5%) were identified. Mutation carriers were diagnosed at a significantly younger age compared with non-carriers (p<0.05). Notably, two patients in our cohort exhibited congenital tooth agenesis, a phenotypical feature rarely reported in patients with HDGC and previously undocumented in East Asian cohorts.Conclusion: Congenital tooth agenesis represents a phenotypic manifestation associated with CDH1 germline mutations. Awareness of such features could enhance recognition of high-risk individuals and support genetic counselling and surveillance strategies. Further studies are needed to confirm these associations.","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145355099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

AUTS2 disruption underlies radioulnar synostosis and skeletal dysmorphogenesis: evidence from four unrelated cases. AUTS2破坏是桡尺关节闭锁和骨骼畸形发生的基础：来自四个不相关病例的证据。

IF 3.7 2区医学

Journal of Medical Genetics Pub Date : 2025-10-20 DOI: 10.1136/jmg-2025-110886

Cheng Liu, Fang Shen, Mei Deng, Chuanchun Yang, Luyang Zhao, Guanghui Zhu, Hua Wang, Zhuo Li, Yongjia Yang

{"title":"AUTS2 disruption underlies radioulnar synostosis and skeletal dysmorphogenesis: evidence from four unrelated cases.","authors":"Cheng Liu, Fang Shen, Mei Deng, Chuanchun Yang, Luyang Zhao, Guanghui Zhu, Hua Wang, Zhuo Li, Yongjia Yang","doi":"10.1136/jmg-2025-110886","DOIUrl":"10.1136/jmg-2025-110886","url":null,"abstract":"Background: While AUTS2 is recognised as a pivotal neurodevelopmental gene, its role in skeletal morphogenesis has remained unexplored. We investigated the contribution of AUTS2 to radioulnar synostosis (RUS) and associated skeletal dysplasias through integrated molecular and phenotypic analyses of unrelated probands.Methods: Comprehensive genetic profiling was performed on patients with RUS, including G-banding karyotyping, translocation breakpoint mapping via low-coverage whole-genome sequencing with PCR/Sanger validation, CNV detection using SNP array (Infinium OmniZhongHua-8) and qPCR, and exome sequencing followed by orthogonal Sanger confirmation.Results: Four novel pathogenic AUTS2 variants were identified from four unrelated patients: a balanced translocation [46,XY,t(7;21)(q11.22;q21.1)] disrupting intron 5 (hg19:chr7:71,845,797); a heterozygous 2.99 Mb deletion (hg19:7q11.22[67,488,531-70,480,818]) spanning AUTS2 and flanking loci; and two de novo frameshift insertions (c.47_48insG; c.864_865insGGACTGTTGCAAAGAGCCA). All variants impaired the full-length AUTS2 transcript. Affected individuals exhibited RUS accompanied by additional skeletal anomalies (micrognathia, short stature, dysplasia of hip joint, tight heel cords) and other AUTS2 syndrome features. Notably, phenotypic overlap with Tsukahara syndrome (OMIM 603438) was observed, suggesting potential diagnostic continuity between these entities.Conclusion: This study establishes AUTS2 as a critical regulator of skeletal development, with molecular disruptions directly linked to RUS pathogenesis and broader skeletal dysmorphogenesis.","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"677-681"},"PeriodicalIF":3.7,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Biallelic loss-of-function variants in C19orf44 lead to retinal degeneration. C19orf44的双等位基因功能丧失变异导致视网膜变性。

IF 3.7 2区医学

Journal of Medical Genetics Pub Date : 2025-10-20 DOI: 10.1136/jmg-2025-110681

Hafiz Muhammad Jafar Hussain, Wang Meng, Yumei Li, Sabika Firasat, Mark E Pennesi, Michael B Gorin, Bin Guan, Rebecca Lynn Clark, Emma Fale-Olsen, Ranya Al Rawi, Aime Agather, Laryssa A Huryn, Paul Yang, Anna Matynia, Rui Chen

{"title":"Biallelic loss-of-function variants in C19orf44 lead to retinal degeneration.","authors":"Hafiz Muhammad Jafar Hussain, Wang Meng, Yumei Li, Sabika Firasat, Mark E Pennesi, Michael B Gorin, Bin Guan, Rebecca Lynn Clark, Emma Fale-Olsen, Ranya Al Rawi, Aime Agather, Laryssa A Huryn, Paul Yang, Anna Matynia, Rui Chen","doi":"10.1136/jmg-2025-110681","DOIUrl":"10.1136/jmg-2025-110681","url":null,"abstract":"Background: Inherited retinal diseases (IRDs) are a group of disorders often resulting in progressive vision loss, ultimately leading to blindness. A significant portion of their genetic causes remain unresolved, partly due to undiscovered disease-associated genes or variants. This study aimed to identify novel genetic links to IRDs.Methods: All patients underwent comprehensive ophthalmological evaluation, including retinal imaging (fundus autofluorescence and macular optical coherence tomography) and electroretinogram testing. Whole exome sequencing and whole genome sequencing were performed on patients with clinically unsolved IRD, and data were analysed using an in-house pipeline to identify causal variants. Subsequently, Sanger sequencing was performed to confirm identified variants.Results: Three unrelated patients from Europe, Middle East and East Asia were identified with unique late-onset retinal degeneration (Stargardt-like phenotype) associated with biallelic loss-of-function (LoF) variants in C19orf44 (HGNC: 26141), a gene of unknown function. The homozygous variant NM_032207.2:c.549_550del;p.Ser185Profs*2 was identified in two unrelated patients (European and Middle Eastern). Moreover, an East Asian patient had likely compound heterozygous LoF variants (NM_032207.2:c.1168C>T;p.Gln390*/c.976_977del;p.Leu326Lysfs*15).Conclusions: Our findings establish C19orf44 as a novel disease-causing gene for IRD with Stargardt-like phenotype, expanding the genetic landscape of retinal degeneration.","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"693-699"},"PeriodicalIF":3.7,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12358183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

First intragenic inversion of CYP11B1 gene causing 11β-hydroxylase deficiency: a molecular diagnosis easily overlooked. CYP11B1基因首次基因内反转导致11β-羟化酶缺乏：一个容易被忽视的分子诊断。

IF 3.7 2区医学

Journal of Medical Genetics Pub Date : 2025-10-20 DOI: 10.1136/jmg-2025-110880

Clément Janot, Kahina Mohammedi, Delphine Mallet, Kévin Choron, Ingrid Plotton, Jordan Teoli, Asmahane Ladjouze, Florence Roucher-Boulez

{"title":"First intragenic inversion of CYP11B1 gene causing 11β-hydroxylase deficiency: a molecular diagnosis easily overlooked.","authors":"Clément Janot, Kahina Mohammedi, Delphine Mallet, Kévin Choron, Ingrid Plotton, Jordan Teoli, Asmahane Ladjouze, Florence Roucher-Boulez","doi":"10.1136/jmg-2025-110880","DOIUrl":"10.1136/jmg-2025-110880","url":null,"abstract":"11β-hydroxylase deficiency (11βOHD) is the second most common cause (5%) of congenital adrenal hyperplasia (CAH). The CYP11B1 gene shares 95% of genomic sequence homology with CYP11B2, and therefore Sanger sequencing remains the gold standard. We present a case of 11βOHD due to an intragenic inversion in CYP11B1 that was missed by both the Sanger sequencing and massive parallel sequencing (MPS) methods. The child was born with virilised genitalia at Prader stage 4 and the biological findings showed a hydromineral retention pattern and a pathognomonic increase in steroid precursors suggestive of 11βOHD. Standard trio analysis revealed only one heterozygous pathogenic variation inherited from the father. The study using MPS showed similar outcomes. Careful observation of the alignment BAM files revealed breaks in sequencing depth, incomplete alignments and systematic paradoxical read-pairs orientation. A specifically designed amplification and Sanger protocol confirmed the novel NM_000497.4(CYP11B1):c.[892_1121+7 inv;1121+8_1121+9del]; p.(Glu298HisfsTer113) variant at heterozygous state in the proband and his mother, fulfilling the diagnosis. The present case reports the first short intragenic inversion in CAH and illustrates the pitfalls that must always be kept in mind when using sequencing methods. When the phenotype is unequivocal, a thorough investigation of the locus should be carried out with cross-use of different techniques.","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"734-738"},"PeriodicalIF":3.7,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exploring the unique characteristics of genes with dual autosomal dominant and recessive inheritance: mechanisms, phenotypes and candidate identification. 探索具有双常染色体显性和隐性遗传的基因的独特特征：机制，表型和候选鉴定。

IF 3.7 2区医学

Journal of Medical Genetics Pub Date : 2025-10-20 DOI: 10.1136/jmg-2025-110872

Shlomit Ezer, Tal Sido, Jonathan Rips, Ronit Hoffman Lipschuetz, Adina Fuchs, Bassam Abu-Libdeh, Elena Chervinsky, Nadirah S Damseh, Nada Danial-Farran, Ilham Morani, Ann Saada, Mohammed Al-Raqad, Somaya Salah, Shira Yanovsky-Dagan, Nadra Samra, Hanna Mandel, Stavit A Shalev, Hagar Mor-Shaked, Joël Zlotogora, Tamar Harel

{"title":"Exploring the unique characteristics of genes with dual autosomal dominant and recessive inheritance: mechanisms, phenotypes and candidate identification.","authors":"Shlomit Ezer, Tal Sido, Jonathan Rips, Ronit Hoffman Lipschuetz, Adina Fuchs, Bassam Abu-Libdeh, Elena Chervinsky, Nadirah S Damseh, Nada Danial-Farran, Ilham Morani, Ann Saada, Mohammed Al-Raqad, Somaya Salah, Shira Yanovsky-Dagan, Nadra Samra, Hanna Mandel, Stavit A Shalev, Hagar Mor-Shaked, Joël Zlotogora, Tamar Harel","doi":"10.1136/jmg-2025-110872","DOIUrl":"10.1136/jmg-2025-110872","url":null,"abstract":"Background: Autosomal dominant (AD) inheritance often arises through haploinsufficiency, dominant-negative or gain of function (GoF) effects, while autosomal recessive (AR) inheritance generally results from partial or complete loss of function (LoF). Yet, a subset of genes demonstrates both inheritance patterns. We aimed to curate a list of such 'AD/AR' genes and to propose additional candidates.Methods: AD/AR genes were subcategorised based on genotype-phenotype correlations and disease mechanisms. Using bioinformatic analyses, we compared genes with AD, AR and AD/AR inheritance across various metrics, including gnomAD constraint values, exon count, protein length, quaternary structure and gene ontology terms. A machine learning-based metric was used to account for interdependence among features.Results: Pathogenic variants in AD/AR genes can lead to distinct or similar phenotypes, depending on the molecular mechanism. AD/AR genes exhibit unique bioinformatic properties such as intermediate constraint scores, a combination of gene ontology terms, a greater average number of exons and an elevated propensity to form homomeric/heteromeric proteins. We identified homozygous LoF or clinically reported variants in nine genes previously classified as AD only.Conclusion: Collectively, the data suggest that AD/AR genes possess distinctive features that likely underpin their dual inheritance modes. We propose nine candidate AD/AR genes and emphasise caution in filtering by inheritance type alone.","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"682-692"},"PeriodicalIF":3.7,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Proposed framework for triage of putative germline variants detected via tumour genomic testing in UK oncology practice. 在英国肿瘤学实践中，通过肿瘤基因组测试检测到的假定种系变异的分类建议框架。

IF 3.7 2区医学

Journal of Medical Genetics Pub Date : 2025-10-20 DOI: 10.1136/jmg-2025-110947

Terri Patricia McVeigh, Helen Hanson, George J Burghel, Clare Turnbull, Katie Snape

{"title":"Proposed framework for triage of putative germline variants detected via tumour genomic testing in UK oncology practice.","authors":"Terri Patricia McVeigh, Helen Hanson, George J Burghel, Clare Turnbull, Katie Snape","doi":"10.1136/jmg-2025-110947","DOIUrl":"10.1136/jmg-2025-110947","url":null,"abstract":"In the UK, most patients receive publicly funded medical care through the National Health Service (NHS), which funds tumour and/or germline testing for eligible patients with cancer to inform clinical management.Testing on tumour-derived DNA may identify putative heritable variants, with implications for the proband and their wider family, but is not a reliable substitute for germline genetic testing when hereditary cancer predisposition is suspected.The likelihood that a variant identified through tumour testing is of germline origin depends on multiple clinical and technical factors. Certain genotypes significantly influence a patient's cancer risk, and intervention in those carriers may facilitate cancer prevention or early detection, while other genotypes are associated with lower cancer risk, and associated intervention in such cases have limited clinical utility.We convened a national meeting of clinical cancer genetics and scientific leads to rationalise germline follow-up testing of variants identified through tumour-based testing. After contrasting potential approaches, implementation of an NHS-contextualised 'intermediate conservative' approach was agreed and refined by the authors, with the final pathway recirculated to the UK clinical and scientific community for consensus agreement and publication.We outline relevant patient, genetic and technical considerations informing likely origin of variants, a review of current relevant guidance and NHS laboratory practices and a workflow for laboratory and clinical teams to triage tumour-detected variants requiring onward germline follow-up. This approach aims to direct limited resources towards identifying germline variants associated with the greatest potential clinical impact, with a view to supporting more efficient and equitable delivery of genomic medicine in oncology.","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"709-719"},"PeriodicalIF":3.7,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Accurate detection of D4Z4 repeats, methylation and allele haplotype in facioscapulohumeral muscular dystrophy 1 using nanopore long-read adaptive sampling sequencing: a pilot study. 利用纳米孔长读自适应采样测序准确检测面肩肱肌营养不良1的D4Z4重复序列、甲基化和等位基因单倍型：一项初步研究

IF 3.7 2区医学

Journal of Medical Genetics Pub Date : 2025-10-20 DOI: 10.1136/jmg-2025-110827

Mingtao Huang, Qinxin Zhang, Sihui Wu, Yixuan Liang, Yan Wang, Zhengfeng Xu, Ping Hu

{"title":"Accurate detection of D4Z4 repeats, methylation and allele haplotype in facioscapulohumeral muscular dystrophy 1 using nanopore long-read adaptive sampling sequencing: a pilot study.","authors":"Mingtao Huang, Qinxin Zhang, Sihui Wu, Yixuan Liang, Yan Wang, Zhengfeng Xu, Ping Hu","doi":"10.1136/jmg-2025-110827","DOIUrl":"10.1136/jmg-2025-110827","url":null,"abstract":"Background: Facioscapulohumeral muscular dystrophy 1 (FSHD1) is one of the most common autosomal dominant neuromuscular diseases. Genetic diagnosis of FSHD1 remains a challenge because of the long length and repetitive nature of D4Z4 repeats. Long-read sequencing is an effective method for detecting FSHD1, but sequencing depth remains a limitation.Methods: We developed a long-read library adaptive sampling (LRL-AS) method based on Oxford Nanopore Technologies (ONT) sequencing to comprehensively detect FSHD1. Two patients were sequenced by adaptive sampling, followed by analyses of D4Z4 repeat units (RUs), methylation and haplotype.Results: Compared with whole-genome sequencing, our LRL-AS method shows significant improvements in both sequencing depth and read length. LRL-AS can identify D4Z4 RUs contraction with accuracy comparable to optical genome mapping in both 4q35 and 10q26 regions. We also calculated methylation levels in the double homeobox 4 (DUX4) gene region. With the benefit of higher sequencing depth, allele-specific methylation can be calculated with greater precision. We also observed that, at different sequencing depths, ONT sequencing data consistently provide stable calculations of methylation levels. More importantly, we demonstrated that data from adaptive sampling can be effectively used to construct the haplotype of the pathogenic allele using single-nucleotide polymorphisms.Conclusion: Our LRL-AS method is a comprehensive approach for FSHD1 detection, improving the accuracy of D4Z4 RUs and methylation detection while enabling allele-specific haplotype construction. It holds promising potential for clinical application.","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"669-676"},"PeriodicalIF":3.7,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Six at Sixty. The revised Ghent nosology for Marfan syndrome turns 15 - what we have gained, what we have missed. 六十六岁。修订后的马凡氏综合征根特分类学已经15岁了——我们得到了什么，也错过了什么。

IF 3.7 2区医学

Journal of Medical Genetics Pub Date : 2025-10-20 DOI: 10.1136/jmg-2025-111239

Bart Loeys, Reihaneh Asadi, Eline Vanaken, Harry Dietz

引用次数: 0